The goal of this Pilot and Feasibility Project is to identify the T-cell subpopulation that is responsible for the initiation of arthritis in the collagen II (CII)-induced DBA/1j mouse model of this disease. The identification of the pathogenic T-cell population will focus on those cells that are resistant to activation-induced cell death (AICD), based on the hypothesis that inefficient AICD of autoreactive T-cell populations leads to the development of autoimmune disease. Preliminary comparative studies of T cells from mice that are susceptible (DBA/lj) or resistant (DBA/2j) to CII-induced arthritis, indicate that splenic T cells from DBA/1j mice stimulated with CII in vitro are more resistant to AICD than their DBA/ 2j counterparts. Use of a cell division tracker dye indicates that the non-apoptotic DBA/1j T cells continue to proliferate and are not anergic. The AICD-resistance of the DBA/1j T cells is not due to altered expression of Fas or Fas ligand but may be associated with an internal defect coupled to the upregulation of NF-kB observed on gel shift analysis of nuclear translocation of NF-kB. The AICD-resistant DBA/1j T cells are enriched in CD4+IFN-g+ T cells, suggesting that the pathogenic T-cell subpopulation is of the Th-1 phenotype. We will first characterize the phenotype of the AICD-resistant DBA/1j T cells and determine if they are necessary and sufficient for the development of CII-induced arthritis. In concurrent studies, we will determine if specific ablation of the CII -reactive CD4+IFN- g+ subpopulation inhibits the development of arthritis in DBA/1j mice. Finally, we will identify the anti-apoptotic molecular mechanisms associated with the upregulation of NF- kB that predispose to CII-induced arthritis. These studies are rendered feasible by our development of a novel gene cell therapy and transgenic mice. The data generated will lead to an improved understanding of the alterations in apoptosis pathways that can contribute to defective AICD and their association with the development of arthritis.